Of prothrombin

Generally, nephrotoxicity is not a problem. Some cephalosporins, especially those with the 3-methylthiotetrazole side chain, such as moxalactam (48), show a tendency to promote bleeding. This appears to be due to a reduction in the synthesis of prothrombin and can be a problem especially in elderly patients, patients with renal insufficiency, or patients suffering from malnutrition (219). The same side chain seems to promote a disulfiramlike reaction in patients consuming alcohol following a cephalosporin dose (80,219). 

Congenital deficiency of prothrombin is inherited in an autosomal recessive fashion and is the rarest of all the hereditary coagulation disorders. Congenital dysprothrombinemia has also been recognized. 

Factor V. High in sialic acid content. Factor V is a large asymmetric single-chain glycoprotein that becomes an active participant in the coagulation cascade when it is converted to its active form by a-thrombin. Approximately 25% of human Factor V is found in the whole blood associated with platelets. Factor V is an essential cofactor along with Factor Xa plus phosphohpid plus Ca " in the conversion of prothrombin to thrombin. 

Calcium is essential to several steps in the enzyme cascade of the blood clotting process, such as the conversion of prothrombin to thrombin (23). Clotting can be inhibited in stored blood suppHes by addition of complexing agents such as EDTA or citrate which reduce the levels of the free ion, Ca(Il). 

Antihemophilic factor [9001-28-9] (AHF) is a protein found in normal plasma that is necessary for clot formation. It is needed for transformation of prothrombin to thrombin. Administration of AHF by injection or infusion can temporarily correct the coagulation defect present in patients with hemophilia. Antihemophilic factor VIII (Alpha Therapeutic) has been approved by the FDA as replacement therapy in patients with hemophilia B to prevent bleeding episodes, and also during surgery to correct defective hemostasis (178). 

The two most widely used coumarins are warfarin (US, Canada, and UK) and phenprocoumon (continental Europe). The long half-life (60 h) of prothrombin means that coumarin cannot achieve therapeutic anticoagulation for at least 5 days following initiation. Thus, for patients with acute thrombosis, oral anticoagulants are usually started only when the patient is receiving a rapidly active agent, usually UFH or LMWH. 

In the case of prothrombin and related clotting factors, interruption of the vitamin K cycle leads to the production of nonfunctional, undercarboxylated proteins, which are duly exported from hepatocytes into blood (Thijssen 1995). They are nonfunctional because there is a requirement for the additional carboxyl residues in the clotting process. Ionized carboxyl groups can establish links with negatively charged sites on neighboring phospholipid molecules of cell surfaces via calcium bridges. 

Table 32-3 summarizes laboratory results obtained on patients with three different causes of jaundice—hemolytic anemia (a prehepatic cause), hepatitis (a hepatic cause), and obstruction of the common bile duct (a posthepatic cause). Laboratory tests on blood (evaluation of the possibihty of a hemolytic anemia and measurement of prothrombin time) and on semm (eg, electrophoresis of proteins activities of the enzymes ALT, AST, and alkahne phosphatase) are also important in helping to distinguish between prehepatic, hepatic, and posthepatic causes of jaundice. 

Prothrombin and several other proteins of the blood clotting system (Factors VII, IX and X, and proteins C and S) each contain between four and six y-carboxygluta-mate residues which chelate calcium ions and so permit the binding of the blood clotting proteins to membranes. In vitamin K deficiency or in the presence of warfarin, an abnormal precursor of prothrombin (preprothrombin) containing little or no y-carboxyglutamate, and incapable of chelating calcium, is released into the circulation. 

Initiation of the fibrin clot in response to tissue injury is carried out by the extrinsic pathway. How the intrinsic pathway is activated in vivo is unclear, but it involves a negatively charged surface. The intrinsic and extrinsic pathways converge in a final common path-vray involving the activation of prothrombin to thrombin and the thrombin-catalyzed cleavage of fibrinogen to form the fibrin clot. The intrinsic, extrinsic, and final common pathways are complex and involve many different proteins (Figure 51-1 and Table 51-1). In... 

Activated by thrombin factor Va is a cofactor in the activation of prothrombin by factor Xa. 

The Final Common Pathway of Blood Clotting Involves Activation of Prothrombin to Thrombin... 

The activation of prothrombin, like that of factor X, occurs on the surface of activated platelets and requires the assembly of a prothrombinase complex, consisting of platelet anionic phospholipids, Ca, factor Va, factor Xa, and prothrombin. 

Figure 51-2. Diagrammatic representation (not to scale) of the binding of factors Va, Xa, Ca +, and prothrombin to the plasma membrane of the activated platelet. The sites of cleavage of prothrombin by factor Xa are indicated by two arrows. The part of prothrombin destined to form thrombin is labeled prethrombin.The Ca " is bound to anionic phospholipids of the plasma membrane of the activated platelet.

Figure 51-3. Diagrammatic representation (notto scale) of prothrombin. The amino terminal is to the left region 1 contains all ten Gla residues. The sites of cleavage by factor Xa are shown and the products named. The site of the catalytically active serine residue is indicated by the solid triangle. The A and B chains of active thrombin (shaded) are held together by the disulfide bridge.

Fig. 2. Generation of tenase and prothrombin complexes. PPL represents the anionic phospholipid surface provided by the platelets (platelet phospholipid). Cleavage of prothrombin by the prothrombinase complex results in the formation of thrombin and the release of a small fragment called prothrombin fragment 1.2 (PFI.2).

Nelsestuen G. L. Role of gamma carboxy glutamic acid. An unusual transition required for calcium-dependent binding of prothrombin to phospholipid. J Biol Chem 1976 251,5648. 

Activated factor X, along with Ca++ ion, factor V, and PF3 (collectively referred to as the prothrombin activator), catalyzes the conversion of prothrombin into thrombin. Thrombin then catalyzes the conversion of fibrinogen into fibrin, an insoluble, thread-like polymer. The fibrin threads form a meshwork that traps blood cells, platelets, and plasma to form the blood clot. The clotting cascade may be elicited by means of two mechanisms (see Figure 16.1) ... 

Both intrinsic and extrinsic pathways generate activated factor X. This protease, in turn, catalyses the proteolytic conversion of prothrombin (factor II) into thrombin (Ha). Thrombin, in turn, catalyses the proteolytic conversion of fibrinogen (I) into fibrin (la). Individual fibrin molecules aggregate to form a soft clot. Factor XHIa catalyses the formation of covalent crosslinks between individual fibrin molecules, forming a hard clot (Figures 12.3 and 12.4). 

Figure 12.5 Proteolytic cleavage of prothrombin by factor Xa, yielding active thrombin. Although prothrombin is a single-chain glycoprotein, thrombin consists of two polypeptides linked by what was originally the prothrombin intrachain disulfide bond. The smaller thrombin polypeptide fragment consists of 49 amino acid residues, and the large polypeptide chain contains 259 amino acids. The N-terminal fragment released from prothrombin contains 274 amino acid residues. Activation of prothrombin by Xa does not occur in free solution, but at the site of vascular damage...

An elevation of prothrombin time was the single most reliable manifestation of cirrhosis. The combination of thrombocytopenia, encephalopathy, and ascites had the highest predictive value. 

There is discussion on the adequacy of tests to identify the hypercoagulable states underlying susceptibility to VTED. The complexity of factors and interactions involved in the hemostatic equilibrium has favored the use of functional tests. Among the several options available the measurement of fragments 1 + 2 (F1 + 2), the amino terminus fragment split during the activation of prothrombin has been widely considered the test of choice. The sparse information available for SERMs, however, is unclear. Raloxifene did not modify... 

The last of the fat-soluble vitamins to be identified was vitamin K, found by Dam to be an anti-hemorrhagic factor for young chicks, distinct from vitamin C. Its structure was determined by Dam in collaboration with Karrer. Interest in the vitamin was intensified when it was discovered (Link, 1941) that dicoumarol, present in spoiled sweet clover, was the agent producing hypothrombinemia (giving prolonged blood-clotting time) in cattle. Since vitamin K is structurally similar to dicoumarol, the vitamin was presumptively implicated in thrombin formation. This has been fully substantiated by recent work on the role of vitamin K in the synthesis of prothrombin in the liver. 

S. W. Tendian, N. L. Thompson, and B. R. Lentz, Calcium-independent binding of prothrombin to negatively charged membranes, Biophys. J. 57, 72a (1990). 

Figure 1-10-3. Vitamin K-Dependent y-Carboxylation of Prothrombin During Translation...

PO loading dose 400 mg tid x 15-30 days, then 200-400 mg qd (5-10 mg/l ) pneurrwnitis when dose >400 mg/d elevation of digoxin level, prolongation of prothrombin time (70-100%) with warfarin pultrwnary fibrosis, hepatitis, ocular opacities proarrhythmic monitor thyroid and liver function... 

The most important adverse effect is bleeding. With coumarins, this can be counteracted by giving vitamin Ki. Coagulability of blood returns to normal only after hours or days, when the liver has resumed synthesis and restored sufficient blood levels of clotting factors. In urgent cases, deficient factors must be replenished directly (e.g., by transfusion of whole blood or of prothrombin concentrate). 

Toxicology. Pindone is a vitamin K antagonist and causes inhibition of prothrombin formation, which results in hemorrhage. 

Warfarin acts as a vitamin K antagonist and suppresses the hepatic formation of prothrombin and of factors VII, IX, and X, causing a markedly reduced prothrombin activity of the blood.Warfarin also causes dilatation and engorgement of blood vessels and an increase in capillary fragility. The two effects can combine to produce hematomas, severe blood... 

It is believed that heparin acts by neutralizing a number of active blood coagulation factors, thus disrupting the transformation of prothrombin into thrombin. Heparin is used to prevent thrombo-formation in myocardial infarctions, thrombosis, and embolism, for maintaining liquid conditions in the blood in artificial blood drcnlation and hemodialysis. Synonyms of this drug are arteven, hepalen, leparan, Uquemin, panheprin, vetren, and many others. 

---